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Nitrated Fatty Acids, Novel Anti-inflammatory Mediator in Allergic Airway Disease

硝化脂肪酸，过敏性气道疾病的新型抗炎介质

基本信息

批准号：
8448650
负责人：
RAJU C REDDY
金额：
$ 31.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448650
关键词：
Ablation Agonist Air Allergens Allergic Animal Model Anti-Inflammatory Agents Anti-inflammatory Asthma Attenuated Biological Bronchoalveolar Lavage Fluid Chemicals Combined Modality Therapy Cyclic AMP Cyclic GMP Data Development Disease Epithelial Cells Fatty Acids Feedback Gene Silencing Genetic Genetically Engineered Mouse Human In Vitro Inflammation Inflammation Mediators Inflammatory Injection of therapeutic agent Interleukin-17 Interleukin-4 Investigation Knock-out Lead Ligands Liquid substance Lung Lung Inflammation Lung diseases Measures Mediating Modeling Mucins Mucous body substance Mus New Agents Nitrates Nitric Oxide Nitric Oxide Synthase Nuclear Nuclear Receptors Peroxisome Proliferator-Activated Receptors Physiological Plasma Play Process Production Protein Isoforms Public Health Reaction Research Role Serum Severities Side Signal Pathway Staging TNF gene Testing Unsaturated Fatty Acids Urine Validation airway hyperresponsiveness allergic airway disease allergic response cell type chemokine cockroach allergen compound 30 cytokine in vivo inhibitor/antagonist novel novel strategies novel therapeutics overexpression public health relevance response transcription factor

项目摘要

ABSTRACT Asthma is a highly prevalent airway disease that is a major public health problem for which available treatment options are inadequate. Endogenous nitrated fatty acids (NFAs), thought to be produced from NO, have recently been identified as important bioactive compounds present in human plasma. Although investigation of their biological activities is at an early stage, evidence is accumulating that they are potent anti-inflammatory molecules. Our preliminary data show that administration of exogenous NFAs can significantly attenuate pathophysiologic manifestations in a murine model of allergic airway disease, whereas inhibiting endogenous NFA synthesis exacerbates allergic responses. NFAs activate the nuclear transcription factor peroxisome proliferator-activated receptor-¿ (PPAR-¿) in some cell types, and we have found that allergic responses are exacerbated when PPAR-¿ is genetically eliminated but are attenuated by overexpression of PPAR-¿ in airway epithelial cells in vivo. Accordingly, we propose to test the hypothesis that activation of airway epithelial cell PPAR-¿ by nitrated fatty acids significantly suppresses the effects of allergic airway disease, including inflammation and mucus production. Our Specific Aims are: 1) to determine the extent to which NFAs modulate PPAR-¿ activity in the lung and the severity of murine allergic airway disease, for which we will use mice constitutively lacking all three isoforms of nitric oxide synthase (triple NOS knockout) and therefore expected to lack NFAs; 2) to determine whether PPAR-¿ activation in airway epithelial cells mediates NFAs' ability to inhibit effects of allergen challenge in murine allergic airway disease, for which we will utilize mice with PPAR-¿ either knocked out or overexpressed selectively in airway epithelial cells; and 3) to determine whether NFAs inhibit chemokine and mucus production in cultured human airway epithelial cells and the extent to which these effects are mediated through PPAR-¿-dependent and/or PPAR-¿-independent mechanisms, for which we will use gene silencing and chemical inhibition to suppress PPAR-¿ while testing for activation of other signaling pathways. For Aims 1 and 2 we will utilize an established murine model of allergic airway disease induced by cockroach allergen, while Aim 3 will be carried out in vitro using well differentiated primary human bronchial epithelial cells grown at an air-liquid interface. Validation of our hypothesis will identify and elucidate the mechanisms through which a novel endogenous substance modulates the severity of allergic airway disease and may lead to new therapeutic avenues and treatments for asthma.

摘要哮喘是一种高度流行的气道疾病，是一个主要的公共卫生问题，选择是不够的。内源性硝化脂肪酸（NFA），被认为是由NO产生的，最近被鉴定为存在于人血浆中的重要生物活性化合物。虽然调查它们的生物学活性尚处于早期阶段，证据正在积累，表明它们具有强效抗炎作用分子。我们的初步数据表明，外源性NFA的管理可以显着减弱在过敏性气道疾病的小鼠模型中的病理生理表现，而抑制内源性 NFA合成加剧过敏反应。NFA激活核转录因子过氧化物酶体增殖物激活受体-<$（PPAR-<$）在某些细胞类型，我们已经发现，过敏反应是当PPAR-²被基因消除时会加剧，但会因气道中PPAR-²的过度表达而减弱体内上皮细胞。因此，我们建议验证气道上皮细胞活化的假设，硝酸化脂肪酸产生的过氧化物酶体增殖物激活物激活物受体（PPAR-1）可显著抑制过敏性气道疾病的影响，包括炎症和粘液产生。我们的具体目标是：1）确定NFAs调节肺中的过氧化物酶体增殖物激活物受体活性和小鼠过敏性气道疾病的严重程度，我们将使用小鼠组成性缺乏一氧化氮合酶的所有三种亚型（三重NOS敲除），因此预期缺乏NFAs; 2）确定气道上皮细胞中的PPAR-β活化是否介导NFAs抑制过敏原激发在小鼠过敏性气道疾病中的作用，我们将使用具有PPAR-的小鼠，在气道上皮细胞中选择性地敲除或过表达;和3）确定NFA是否抑制在培养的人气道上皮细胞中趋化因子和粘液的产生以及这些趋化因子和粘液在多大程度上效应是通过PPAR依赖性和/或PPAR非依赖性机制介导的，为此，我们将使用基因沉默和化学抑制来抑制PPAR-γ，同时检测其他信号的激活途径。对于目的1和2，我们将利用已建立的过敏性气道疾病的小鼠模型，蟑螂变应原，而Aim 3将在体外使用分化良好的原代人支气管在气液界面生长的上皮细胞。验证我们的假设将确定和阐明一种新的内源性物质调节过敏性气道疾病严重程度的机制并可能导致哮喘的新的治疗途径和治疗。